Type 1 diabetes has traditionally been treated by life-long insulin therapy or pancreas transplantation. However, frequent episodes of hypoglycemia are common in patients on life-long insulin therapy. And whole pancreas transplantation is an invasive surgical procedure with significant risks. Islet cell transplantation is an attractive alternative to the traditional treatments of type 1 diabetes. However, two of the major limiting factors in the widespread use of islet cell transplantation clinically are the availability of a sufficient number of islets and the inability of current immunosuppressive treatments to protect transplanted islets long-term.
As of 2005 an estimated 1.4 to 2.8 million people in the United States were diagnosed with insulin dependent diabetes (Collaborative Islet Transplant Registry, 5th Annual Report, Bethesda, Md.: National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 2008). According to a 2007 report by the United Network for Organ Sharing (UNOS), only 1,931 pancreatic donors were reported (United Network of Organ Sharing; Donors Recovered in the U.S. by Donor Type. Washington, D.C.: United States Department of Health and Human Services, 2009). Of those, 1,363 were used for whole pancreas transplantation. Because islet transplantation is still an experimental procedure, priority of donor pancreata goes to whole organ transplant. Thus, only 568 pancreata would have been available in 2007 for islet cell transplantation. In addition to this already limited availability of pancreata for islet transplantation, most islet transplant recipients require more than one donor in order to acquire a sufficient number of islet cells to achieve insulin independence. This limits the number of people who could be helped by islet cell transplantation even more. Alternative sources of islet cells or development of a method for β-cell regeneration are essential to the widespread use of islet transplantation in treating type 1 diabetes.
Despite using 2-3 pancreata for each recipient, however, results reported by the Edmonton group have shown that the rate of success for functional islet grafts in the clinical setting is approximately 80% after 1 year, but only 10% after 5 years (Ryan et al, Diabetes, 54(7):2060-2069 (2005); Shapiro et al, N Engl J Med, 343(4):230-238 (2000)). Effects of both auto- and allogeneic immune responses severely limit the long-term success of islet grafts, even when an abundant number of islets have been transplanted. Thus, development of an immunosuppressive treatment strategy that protects islets long-term is necessary for the overall success of this procedure.
Many immunosuppressive protocols used in islet cell transplantation to date have relied on calcineurin inhibitors that have been shown to negatively affect pancreatic β-cell function and insulin sensitivity. Therefore, despite offering protection from host immune attack, these agents themselves can diminish graft function and contribute to failure of the transplanted islets. Additionally, recipients of islet grafts still demonstrate the auto-immune effects of diabetes development that led to their disease initially, thereby affecting function of transplanted islets long-term.
GLP-1 receptor agonists (such as exenatide, lixisenatide, liraglutide, albiglutide, dulaglutide, taspoglutide) bind to the GLP-1 receptor on beta cells and have been shown to improve insulin secretion in response to glucose in addition to protecting beta cells from apoptosis and promoting beta cell regeneration in animals. Shalev et al, Horm Res, 49(5):221-225 (1998); Chen et al, Biochem Biophys Res Comm, 346:1067-1074 (2006); Xu et al, Diabetes, 48:2270-2276 (1998); Tourrel et al, Diabetes, 50:1562-1570 (2001); Couto et al, Metabolism Clinical and Experimental, 56:915-918 (2007). Studies in NOD mice have also shown that pre-treatment of islet recipients with a DPPIV-inhibitor can alter T-cell migration to islets. Kim et al, Diabetes, 58:641-651 (2009).
Because of the drawbacks of conventional immunosuppressive therapy, there is a need in the art for an effective form of treatment to allow for long-term islet graft function. The disclosure is directed to the unexpected discovery that GLP-1 receptor agonists can meet this need.